The present invention relates to a process for the preparation of ipidacrine (i.e., 9-amino-2,3,5,6,7,8-hexahydro-lH-cyclopenta [b]quinoline) and ipidacrine hydrochloride hydrate (i.e., 9-amino-2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]quinoline hydrochloride hydrate).
Ipidacrine hydrochloride hydrate has been reported as a compound having a stimulating effect of transmission at the peripheral nervous system (for example, see JP-B (Kokoku)-63-35611). Further, it has been reported as a compound showing improvement in learning and memory (for example, see JP-B (Kokoku)-3-54922).
As a synthetic process for ipidacrine hydrochloride hydrate, 2-amino-1-cyclopentene-1-carbonitrile (or 1-amino-2-cyanocyclopentene-1) and cyclohexanone are first heated under reflux with polyphosphoric acid in dry benzene to obtain ipidacrine (i.e., 9-amino-2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]quinoline) and hydrogen chloride gas is then passed through the ethanol solution of the resultant reaction mixture to yield ipidacrine hydrochloride hydrate (i.e., 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b]quinoline-hydrochloride hydrate) has been reported (for example, see JP-B (Kokoku)-63-35611). Further, it is described that ipidacrine is obtained even if reacting 5,5-pentamethylen-7-oxo-1,2,3,4,6,7-hexahydrocyclopenta [d]pyrimidine obtained as a byproduct in the above reaction with phosphorus oxychloride in toluene (for example, see JP-B (Kokoku)-3-54922).
Further, according to the specification of Japanese Patent No. 2510586, the synthetic method of reaction of 2-amino-1-cyclopentene-1-carbonitrile and cyclohexanone in a solvent such as chloroform in the presence of ethyl polyphosphate at 20 to 100xc2x0 C. is disclosed.
According to the description in this patent specification, ethyl polyphosphate is prepared by the reaction of diethyl ether and diphosphorus pentaoxide in chloroform.
In order to synthesize ipidacrine hydrochloride hydrate using the method described in the above JP-B-63-35611 or JP-B-3-54922, it is necessary to remove the 5,5-pentamethylene-7-oxo-1,2,3,4,6,7-hexahydrocyclopenta [d]pyrimidine obtained as an impurity during the process, the yield is decreased. Further, the impurity, 5,5-pentamethylene-7-oxo-1,2,3,4,6,7-hexahydrocyclopenta [d]pyrimidine, can be reacted with phosphorus oxychloride according to JP-B (Kokoku)-3-54922 to form ipidacrine hydrochloride hydrate, but such processing is not suitable for mass production, since the number of reaction steps is increased, etc.
Further, the process described in Japanese Patent No. 2510586 is not suitable for industrial-scale mass production, since the procedure for using the highly flammable and hazardous diethyl ether for the preparation of ethyl polyphosphate is extremely complicated and, in addition thereto, a long time (e.g., 3 days) is taken for the preparation. Further, the ethyl polyphosphate prepared has a high viscosity and, therefore, is inconvenient in handling, and also easily changes over time, and therefore, there is the disadvantage that the successive supply of the product having constant quality is extremely difficult. Further, chloroform is used as a reaction solvent, but the use of a large amount of chloroform, which is a type of halomethane, in industrial preparation is a problem in terms of not only work, but also the environment. Therefore, it is hard to say that it is a desirable process.
Further, the ipidacrine generated in the reaction solution after the dehydration condensation reaction in chloroform is separated and purified by a method of addition of water to convert the product to a salt and transfer the same to an aqueous phase, then the aqueous phase is made alkali to precipitate the crystal. However, the chloroform dissolve a considerable amount of the salt of ipidacrine, and therefore, for a increasing of the yield by this method, the chloroform phase should be washed several times (4 times or more). Therefore, this causes the disadvantage of a large number of operation steps.
Further, according to the above three publications, when ipidacrine is hydrochlorated to produce ipidacrine hydrochloride hydrate, ethanol is used as a solvent and hydrogen chloride gas is used as an agent for hydrochlorination. When using an alcoholic solvent such as ethanol as a solvent, a considerable amount of the residual solvent is partially included in the ipidacrine hydrochloride hydrate generated instead of water of crystallization and, therefore, ipidacrine hydrochloride hydrate with insufficient amount of water of crystallization is obtained. The infrared spectrum of this crystal is not idertical with the spectral chart of the standard product and change in the crystal form by X-ray structural analysis, etc. can be observed (for example, see Iyakuhin Kenkyu 28, 9, 643-657 (1997)).
Further, since hydrogen chloride gas, which is highly toxic and complicated to handle, is used as an agent for hydrochlorination, the handling cannot be said at all to be easy. Therefore, it is difficult to say that the process is desirable.
Accordingly, an object of the present invention is to provide a process for the preparation of ipidacrine or ipidacrine hydrochloride hydrate without having the above disadvantages and further in a good yield.
The present inventors engaged in intensive studies to find a process for the preparation of ipidacrine in a good yield, further with little dangerous, easy to carry out, and with little problems in terms of the environment and, as a result, found that these problems were able to be solved by using as a dehydration condensing agent ethyl polyphosphate obtained by reacting diphosphorus pentaoxide with triethyl phosphate and ethanol in a hydrocarbon-based solvent without isolation, conducted further research, whereby the present invention was completed.
Further, we found that in the hydrochlorination step of ipidacrine, by using concentrated hydrochloric acid in an acetone solvent for of hydrochlorination, an ipidacrine hydrochloride hydrate without any change in infrared spectrum or crystal form by X-ray structural analysis is obtained, conducted further research, whereby the present invention was completed.
In accordance with the present invention, there is provided a process for the preparation of ipidacrine (i.e., 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta [b]quinoline) having the formula (I): 
comprising reacting diphosphorus pentaoxide with trialkyl phosphate and a compound having a hydroxyl group in a hydrocarbon-based solvent so as to prepare a polyphosphate ether partially having a hydroxyl group, as a dehydration condensing agent, then using polyphosphate ester thus obtained, without isolation, for a dehydration condensation reaction of 2-amino-1-cyclopentene-1-carbonitrile and cyclohexanone.
In accordance with the present invention, there is also provided a process for the preparation of ipidacrine hydrochloride hydrate comprising of the reaction of ipidacrine with concentrated hydrochloric acid in acetone or in a mixed solvent of acetone with a small amount of water for hydrochlorination.
In accordance with the present invention, there is further provided a process for the preparation of ipidacrine hydrochloride hydrate, wherein the ipidacrine hydrochloride hydrate shows an infrared absorption spectrum of a standard product without containing residual solvent (Type A).